Method for removing residual organic solvent in solid dispersion containing thermosensitive and indissolvable medicine

Abstract

The invention discloses a method for removing a residual solvent in a solid dispersion containing a thermosensitive and indissolvable drug, which comprises the following steps: 1) dissolving or dispersing the drug and a carrier in a mixed solvent of an organic solvent and water, heating to 50-65 DEG C, stirring within no more than 1 hour until the drug and the carrier are dissolved, and filtering to obtain a filtrate; wherein the weight percentage of the water in the total solvent is 3-64%; (2) preparing a solid dispersion from the solution obtained in the step (1) through a spray drying technology; (3) preparing the solid dispersion product obtained in the step (2) at 40-60 DEG C under the vacuum degree gt; and carrying out vacuum drying for not more than 72 hours under the condition of-0.09 Mpa to obtain the solid dispersion with qualified solvent residue. According to the method for removing the residual solvent, the thermosensitive and indissolvable drug and the carrier are dissolved by adopting the mixed solvent of the organic solvent and the water, and the spray drying and secondary drying modes are adopted, so that the removal rate of the residual solvent can be effectively improved, and meanwhile, the drug molecules cannot be further crystallized; the amorphous state is still kept.

Description

Technical Field

[0001] The invention belongs to the field of pharmaceutical production, and in particular relates to a method for removing residual organic solvents in a solid dispersion containing a heat-sensitive and poorly soluble drug. Background Art

[0002] In recent years, high-throughput screening and combinatorial chemistry have promoted the development of new drugs. These two methods focus on evaluating the biological activity of molecules when conducting drug screening, and often ignore the physical and chemical properties that affect their drugability. The physical and chemical properties of compounds determine the bioavailability of drugs, as well as their distribution, metabolism and clearance in the body. According to statistics, in the process of new drug development, about 40% of drugs under development and 70% of synthetic drugs screened by high-throughput screening are poorly soluble drugs. Poor water solubility will lead to large fluctuations in absorption and low bioavailability after oral administration. In order to effectively solve the problem of poor solubility of drugs, scientific researchers in the field of pharmaceuticals have designed and developed a variety of solubilization technologies, such as making solid dispersions, micronization, salt formation, and the use of nanotechnology, and some products have been successfully developed and marketed.

[0003] The preparation of solid dispersions is a very important solubilization process.

[0004] According to incomplete statistics, there are more than 30 kinds of solid dispersion drugs approved by FDA at present, among which many new molecular entities have poor thermal stability and cannot be prepared by solvent-free hot melt extrusion. Solid dispersions are mainly prepared by solvent spray drying. Many candidate drugs have poor solubility in three types of solvents with lower toxicity, so it is often necessary to use two types of solvents with higher toxicity such as methanol, dichloromethane and tetrahydrofuran to obtain a clear solution for spray drying. Organic solvents with higher toxicity need to be removed below the limit specified by ICH. Common solvent removal methods include spray drying (such as Chinese patent documents CN103610646A and CN105616365A), fluidized bed drying (such as Chinese patent document CN105616365A), blast oven drying, vacuum drying, supercritical fluid method (such as Chinese patent document CN103585122A), etc. Most of the organic solvents can be removed in a short time by these methods, and the drying efficiency is higher. However, the above-mentioned methods such as spray drying cannot completely and effectively remove organic solvents, and sometimes fail to reach the limit specified by ICH. CN103610646A reports that the spray drying method removes residual solvents at an inlet temperature of 100-110 degrees, but due to the high temperature, it is not suitable for thermally unstable candidate drugs. Supercritical fluids cannot take away solvent residues that are tightly complexed with hydrogen bonds. Freeze drying is more suitable for samples with good water solubility, but candidate drugs that use solid dispersions to solve solubility problems are often compounds that are extremely difficult to dissolve in water. They can only be dissolved in suitable organic solvents with good volatility. The poor water solubility of candidate drugs limits the use of freeze drying methods in solid dispersion preparations.

[0005] For thermosensitive drugs, high temperature spray drying can easily lead to drug degradation in order to remove residual solvents; for some Class II solvents with lower residual limits such as acetonitrile, dichloromethane, tetrahydrofuran, etc., how to remove organic solvents during the post-processing of samples, especially how to ensure that residual solvents meet the requirements of ICH guidelines, is still a difficult problem. In addition, extending the drying time to remove residual solvents will lead to solid aging and quality risks. In addition, low production efficiency will increase manufacturing costs and is not conducive to energy conservation and emission reduction. Summary of the invention

[0006] Objective of the present invention: The objective of the present invention is to provide a method for removing residual solvents in a solid dispersion containing a heat-sensitive and poorly soluble drug, wherein the removal method is performed as follows:

[0007] 1) dissolving the heat-sensitive and poorly soluble drug and the carrier in a mixed solvent of an organic solvent and water, heating to 50-65° C., stirring until dissolved within no more than 1 hour, wherein the weight percentage of water in the total solvent is 3-64%, to obtain a clear solution;

[0008] 2) The solution obtained in step 1) is spray-dried to prepare a solid dispersion, wherein the spray-drying parameters are as follows:

[0009] Equipment parameters Parameter information Inlet air temperature 80～90℃ Air outlet temperature 45～60℃ Pump speed 18～20％ Nitrogen pressure 45％ Fan frequency 80～95％

[0010] 3) The solid dispersion product obtained in step 2) is vacuum dried at 40-60° C. and under a vacuum degree of >-0.09 MPa for no more than 72 hours to obtain a solid dispersion with qualified solvent residue.

[0011] Preferably, the solid dispersion includes a drug and a carrier, the carrier is selected from copovidone VA64, povidone K25, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyvinyl pyrrolidone, etc., the drug is a heat-sensitive drug that is poorly soluble in water, including but not limited to sorafenib, regorafenib, enzalutamide, ritonavir, everolimus, troglitazone, nimodipine, rosuvastatin calcium, etc., and the mass ratio of the drug to the carrier is 1:2 to 1:8, preferably 1:3 or 1:4.

[0012] Preferably, the organic solvent in step 1) is tetrahydrofuran, dichloromethane or acetonitrile, preferably tetrahydrofuran.

[0013] Preferably, in step 3), vacuum drying is performed at 45-50°C.

[0014] Preferably, the vacuum degree in step 3) is >-0.1Mpa.

[0015] Preferably, the vacuum drying in step 3) is performed for no more than 48 hours.

[0016] Beneficial Effects

[0017] The residual solvent removal method according to the present invention adopts a mixed solvent of an organic solvent and water to dissolve the heat-sensitive and poorly soluble drugs and carriers and adopts spray drying and secondary drying methods, which can effectively improve the removal rate of the residual solvent, while ensuring that the drug molecules will not undergo further crystallization and remain in an amorphous state. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] In order to more clearly illustrate the specific implementation methods of the present invention or the technical solutions in the prior art, the drawings required for use in the specific implementation methods or the description of the prior art will be briefly introduced below. Obviously, the drawings described below are some implementation methods of the present invention. For ordinary technicians in this field, other drawings can be obtained based on these drawings without paying any creative work.

[0019] Figure 1 This is the XRPD pattern of raw material sorafenib before spray drying;

[0020] Figure 2 This is the XRPD pattern of raw material regorafenib before spray drying;

[0021] Figure 3 is an XRPD pattern of regorafenib in a solid dispersion treated by the method of Example 1;

[0022] Figure 4 This is the XRPD pattern of regorafenib in the solid dispersion treated by the method of Example 2;

[0023] Figure 5 is an XRPD pattern of sorafenib in a solid dispersion treated by the method of Example 3;

[0024] Figure 6 is an XRPD pattern of regorafenib in a solid dispersion treated by the method of Comparative Example 1;

[0025] Figure 7 This is the XRPD pattern of sorafenib in the solid dispersion treated by the method of Comparative Example 2. DETAILED DESCRIPTION

[0026] Hereinafter, the present invention will be described in detail. Before describing, it should be understood that the terms used in this specification and the appended claims should not be interpreted as being limited to the general meaning and dictionary meaning, but should be interpreted according to the meaning and concept corresponding to the technical aspects of the present invention on the basis of the principle that the inventor is allowed to appropriately define the terms for the best interpretation. Therefore, the descriptions presented here are only preferred examples for illustrative purposes and are not intended to limit the scope of the present invention, so that it should be understood that other equivalents or improvements can be obtained therefrom without departing from the spirit and scope of the present invention.

[0027] In this document, the terms "include", "including", "have", "contain" or any other similar terms are open conjunctions, which are intended to cover non-exclusive inclusions. For example, a composition or product containing multiple elements is not limited to the elements listed herein, but may also include other elements that are not explicitly listed but are generally inherent to the composition or product. In addition, unless otherwise explicitly stated, the term "or" refers to an inclusive "or" rather than an exclusive "or". For example, any of the following situations satisfies the condition "A or B": A is true (or exists) and B is false (or does not exist), A is false (or does not exist) and B is true (or exists), and A and B are both true (or exist). In addition, in this document, the interpretation of the terms "include", "including", "have", and "contain" should be considered to have been specifically disclosed and simultaneously cover closed or semi-closed conjunctions such as "consisting of" and "consisting essentially of".

[0028] In this article, all features or conditions defined in the form of numerical ranges or percentage ranges are only for brevity and convenience. Accordingly, the description of numerical ranges or percentage ranges should be deemed to have covered and specifically disclosed all possible secondary ranges and individual values ​​within the range, especially integer values. For example, the range description of "1 to 8" should be deemed to have specifically disclosed all secondary ranges such as 1 to 7, 2 to 8, 2 to 6, 3 to 6, 4 to 8, 3 to 8, etc., especially secondary ranges defined by all integer values, and should be deemed to have specifically disclosed individual values ​​such as 1, 2, 3, 4, 5, 6, 7, 8, etc. within the range. Unless otherwise specified, the above interpretation method applies to all contents of the entire present invention, regardless of whether the range is broad or not.

[0029] If the quantity or other numerical value or parameter is expressed as a range, a preferred range or a series of upper and lower limits, it should be understood that all ranges consisting of any upper limit or preferred value of the range and the lower limit or preferred value of the range have been specifically disclosed herein, regardless of whether these ranges are disclosed separately. In addition, if a numerical range is mentioned herein, unless otherwise specified, the range should include its endpoints and all integers and fractions within the range.

[0030] In this document, under the premise of achieving the purpose of the invention, numerical values ​​should be understood to have the accuracy of the number of significant digits of the numerical value. For example, the number 40.0 should be understood to cover the range from 39.50 to 40.49.

[0031] In the prior art, for drugs with extremely poor water solubility, organic solvents are often required for dissolution, such as Class II solvents such as acetonitrile, dichloromethane, tetrahydrofuran, etc., but since these organic solvents are often more firmly combined with the surface of drug molecules through hydrogen bonds and the like, the general spray drying method cannot effectively remove these organic solvents. Further high-temperature drying is often required to further remove the residual organic solvent. However, long-term high-temperature drying treatment often causes the drug molecules to change from amorphous to crystalline form or chemically degrade, which is not conducive to the solubility and corresponding dissolution of the drug. Pharmaceutical properties, but the drying temperature is not high and the residual organic solvent cannot be effectively removed. This has always been a contradiction in the pharmaceutical field, especially for those heat-sensitive (thermally unstable) and water-insoluble drugs.

[0032] Take tetrahydrofuran as an example. It is a commonly used solvent for organic synthesis and is often used in combination with butyl lithium. Tetrahydrofuran can be complexed with borane and used as a borane solution for commercial production, storage, transportation and use. Tetrahydrofuran also has good solubility for some poorly soluble candidate drugs and plays an irreplaceable role. There are many heteroatoms such as nitrogen atoms and oxygen atoms in drug molecules. Commonly used solid dispersion matrices such as povidone, copovidone, hydroxypropyl methylcellulose acetate succinate (HPMCAS), polyethylene caprolactam-polyvinyl acetate-polyethylene glycol graft copolymer (Soluplus), etc. all contain many heteroatoms. In order to dissolve APIs and polymer materials, tetrahydrofuran is required as a solvent. Hydrogen bonds are easily formed between tetrahydrofuran and drug molecules and polymer materials. The bonds in some solid dispersion prescriptions are relatively strong, which makes it difficult to remove them to the level below ICH requirements (not exceeding 720 ppm) through spray drying and secondary drying. This poses a challenge to the later scale-up production of candidate drugs, resulting in a significant increase in the drying time during production, and the secondary drying time is also extended. In the future, industrial scale-up production will take longer, which invisibly greatly extends the production cycle and increases production costs. In addition, excessive drying time increases the risk of solid dispersion aging, which may bring risks to clinical patients' medication, namely, the potential risk of tetrahydrofuran exceeding the standard and the potential possibility of solid dispersion aging, which in turn affects the quality of the drug and the subsequent development of candidate drugs.

[0033] At present, poorly soluble candidate drugs account for more than 70%, many of which are molecules containing heteroatoms. In the process of using solid dispersions to solve the drugability, it is often necessary to use a second type of organic solvent for dissolution, and the second type of solvents such as dichloromethane, methanol or tetrahydrofuran, because the residual limit requirements are high, when the solvent is easy to form a relatively close combination with the API and / or the polymer solid dispersion matrix, it is difficult to remove the spray drying, and it is difficult to meet the standards; or in order to meet the standards, it is necessary to use a very high temperature spray drying or a high temperature and a long time of secondary vacuum drying, which virtually prolongs the production cycle, resulting in low production efficiency, and can increase the risk of solid dispersion aging in large-scale production, affect the stability of solid dispersion preparations, shorten the shelf life, and is not conducive to the drugability safety evaluation of new drugs, as well as the later development of new drugs. The present invention introduces a certain amount of water into the spray drying solution by studying that at a lower spray drying temperature, through suitable secondary drying conditions, such as low temperature, short time, etc., it can meet the standards, and greatly shorten the drying time while ensuring that the drug molecules do not change (for example, maintaining an amorphous state, etc.). In another example, if the residual solvent is not tightly bound to the active ingredient or polymer material and can meet the standard, adding an appropriate amount of water for spray drying can also significantly reduce the actual residual level of the solvent in the solid dispersion preparation to far below the limit requirement, thus ensuring the safety of patients' medication.

[0034] In step 1) of the method for removing residual solvents in a solid dispersion containing a thermosensitive and poorly soluble drug according to the present invention, the thermosensitive and poorly soluble drug and the carrier are dissolved or dispersed in a mixed solvent of an organic solvent and water, heated to 50-65° C., and stirred within no more than 1 hour until dissolved, wherein the weight percentage of water in the total solvent is 3-64%, wherein if the weight percentage of water in the total solvent is less than 3%, the removal effect of the residual organic solvent is poor; if it is higher than 64%, since both the drug and the carrier are poorly soluble in water, the product cannot be completely dissolved, which makes it difficult to carry out the subsequent steps.

[0035] In step 3) of the method for removing residual solvents in a solid dispersion containing a thermosensitive and poorly soluble drug according to the present invention, the solid dispersion product obtained in step 2) is vacuum dried at 40-60° C., preferably 45-50° C., under a vacuum degree of >-0.1 MPa, preferably a vacuum degree of >-0.1 MPa, for no more than 72 hours, preferably no more than 48 hours, to obtain a solid dispersion with qualified residual solvent.

[0036] In order not to affect the solubility of the amorphous solid dispersion and the dissolution of the subsequent solid dispersion preparation, as well as the stability of the later preparation, the drying temperature in step 3) cannot be too high, and the drying time can be controlled to not exceed 72 hours, for example, within 2-3 days, otherwise it will affect the production efficiency.

[0037] In addition, unless otherwise specified, among the reagents and solvents disclosed below, tetrahydrofuran was purchased from Shanghai Yanrui Chemical Technology Co., Ltd., povidone K25 was purchased from Tianjin Sanjian Trading Co., Ltd., regorafenib was provided by Yaoyuan Pharmaceutical Chemistry (Shanghai) Co., Ltd., sorafenib was purchased from Anaiji Chemical, and copolyvidone VA64 was purchased from Shanghai Yuanhong Chemical Co., Ltd. Residual solvent detection Agilent Technoliges' 7890A series GC system with FID detector and 7697A headspace sampler. Spray drying was carried out using a Buchi B-290 small spray dryer from BUCHI Labortechnik AG. XRPD was detected using a Bruker D8 ADVANCE series powder diffractometer from Bruker, Germany.

[0038] The following examples are only listed as examples of embodiments of the present invention and do not constitute any limitation to the present invention. It can be understood by those skilled in the art that modifications within the scope of the essence and concept of the present invention fall within the scope of protection of the present invention. Unless otherwise specified, the reagents and instruments used in the following examples are all commercially available products.

[0039] Residual solvent analysis method:

[0040] 1. Overview

[0041] Project Code RD31ZJ1 Test Type Solvent residue Analysis object RD31 solid body principle Determination of methanol and tetrahydrofuran residues in RD31 solid fraction by external standard method (w / w)

[0042] 2. Instruments, equipment and consumables

[0043] Agilent 7890A GC system with FID detector and Agilent 7697A headspace sampler or equivalent GC system

[0044] Electronic analytical balance (one hundred thousandth)

[0045] Chromatographic column: Agilent DB-624 60m×0.32mm, 1.8μm (PN:123-1364)

[0046] A-grade volumetric flask (50ml and 100ml) and pipette (1.0ml)

[0047] 20ml headspace bottle

[0048] 3. Reagents

[0049] N-Methylpyrrolidone (NMP), GC-HS grade

[0050] Methanol, analytical grade or better

[0051] Tetrahydrofuran, analytical grade or higher

[0052] 4. Solution Preparation

[0053] 4.1 Diluent and blank solution

[0054] Diluent: NMP

[0055] Blank solution: accurately measure 1.0 ml of diluent, place in a 20 ml headspace bottle, and seal. Mark as BLANK. Each injection bottle can only be injected once. For repeated injections, separate injection bottles must be prepared.

[0056] 4.2 Reference substance stock solution 1

[0057] Prepare 1 portion (containing about 3 mg / ml methanol and about 0.72 mg / ml tetrahydrofuran)

[0058] Accurately weigh about 300 mg of methanol and about 72 mg of tetrahydrofuran, place them in a 100 ml volumetric flask (already filled with an appropriate amount of NMP), dilute to the scale with NMP, and shake well.

[0059] 4.3 Reference solution

[0060] Prepare 1 portion (containing about 0.3 mg / ml methanol and about 0.072 mg / ml tetrahydrofuran). Label as STD.

[0061] Accurately measure 5.0 ml of the reference stock solution, place it in a 50 ml volumetric flask, dilute to the mark with NMP, and shake well.

[0062] Each injection bottle can only be used for injection once. For repeated injections, separate injection bottles must be prepared.

[0063] 4.4 Test solution

[0064] Two aliquots (containing about 100 mg / ml of the main component) were prepared and labeled as SPL-1 and SPL-2.

[0065] Take about 100 mg of this product, weigh it accurately, put it in a 20 ml headspace bottle, add 1.0 ml of diluent to dissolve it, and seal it.

[0066] Each injection bottle can only be used for injection once. For repeated injections, separate injection bottles must be prepared.

[0067] 5. Testing Procedure

[0068] 5.1 Chromatographic conditions

[0069]

[0070] 5.2 Sample analysis

[0071]

[0072]

[0073] 5.3 System suitability

[0074]

[0075] 6. Calculation method

[0076] 6.1 Points

[0077] For blank solution, reference solution and test solution, only integrate the peak to be measured.

[0078] Determine the retention time of each analyte based on the reference solution.

[0079] 6.2 Calculation of residual solvent content

[0080] 6.2.1. Calculate the methanol and tetrahydrofuran residues according to the following formula

[0081]

[0082] Where:

[0083] A spl : Peak area of ​​methanol and tetrahydrofuran in each test solution;

[0084] A std : Average peak areas of methanol and tetrahydrofuran in reference solution for 6 consecutive times;

[0085] W std : The weight of methanol and tetrahydrofuran in the reference solution, mg;

[0086] W spl : The weight of the test sample, mg.

[0087] Example

[0088] In order to demonstrate the effect of the present invention, the anti-tumor drug regorafenib was used as a research model compound to compare the spray drying schemes with and without adding water, and the effect of removing the residual solvent after secondary drying.

[0089] In addition, unless otherwise specified, the spray dryer used in the following examples is from Buchi, and the equipment name is: Buchi small spray dryer, model: Buchi B-290. The residual solvent is detected using an Agilent 7890A GC system with a FID detector and an Agilent 7697A headspace sampler or an equivalent gas chromatography system.

[0090] Example 1

[0091] prescription:

[0092]

[0093]

[0094] Process: Add 250ml of tetrahydrofuran and 240ml of water to the reaction bottle, place it in a water bath and heat it to 55°C, then add 1.5g of regorafenib, continue stirring at about 55°C for about 10 minutes until the solid dissolves, then add 6.0g of povidone K25, continue stirring for 50 minutes until the solution is clear. The solution is spray dried. The spray drying conditions are as follows:

[0095] Equipment parameters Parameter information Inlet air temperature 80～90℃ Air outlet temperature 45～60℃ Pump speed 18～20％ Nitrogen pressure 45％ Fan frequency 80～95％

[0096] The spray-dried product was placed in a vacuum drying oven, evacuated to -0.095 MPa, and vacuum dried at about 50°C. Samples were taken and tested for residual solvents at about 24h and 48h. The results are shown in Table 1.

[0097] Figure 3 is the XRPD pattern of regorafenib in solid dispersion prepared by the method of this embodiment. Figure 2 Compared with the XRPD pattern of the raw material regorafenib before spray drying, the regorafenib in the solid dispersion prepared by the method of this embodiment is amorphous, which can effectively improve the dissolution properties of the drug regorafenib compared with the raw material regorafenib with high crystallinity.

[0098] Example 2

[0099] The prescription is as follows:

[0100] Name of raw materials prescription percentage Function factory Regorafenib 1.5g 20％ Active ingredients self made Povidone K25 6g 80％ Solid matrix Tianjin Sanjian Trading Tetrahydrofuran 230ml / Solvents Yanrui Chemical water 350ml / Solvents Tap water

[0101] Process: Add 200ml of tetrahydrofuran to the reaction bottle, place it in a water bath and heat it to 55°C, then add 1.5g of regorafenib, and then add 6.0g of povidone K25 to partially dissolve. Control the temperature at around 55°C and add 200ml of water to the reaction solution, stir for about 7 minutes and the reaction solution becomes clear. Continue to add 150ml of water to the reaction system, and the reaction solution becomes turbid again. Continue to add 30ml of tetrahydrofuran to the reaction solution to make the reaction solution clear again. Spray dry the solution. The spray drying conditions are as follows:

[0102] Equipment parameters Parameter information Inlet air temperature 80～90℃ Air outlet temperature 45～60℃ Pump speed 18～20％ Nitrogen pressure 45％ Fan frequency 80～95％

[0103] The spray-dried product was placed in a vacuum drying oven, evacuated to -0.095 MPa, and vacuum dried at about 50°C. Samples were taken and tested for residual solvents at about 24h and 48h. The results are shown in Table 1.

[0104] Figure 4 is the XRPD diagram of regorafenib in solid dispersion after being treated by the method of this embodiment. Figure 2Compared with the XRPD pattern of the raw material regorafenib before spray drying, the regorafenib in the solid dispersion treated by the method of this embodiment is amorphous, which can effectively improve the dissolution properties of the drug regorafenib compared with the raw material regorafenib with high crystallinity.

[0105] Comparative Example 1

[0106] The prescription is as follows:

[0107] Name of raw materials prescription percentage Function factory Regorafenib 1.5g 20％ Active ingredients self made Povidone K25 6.0g 80％ Solid matrix Tianjin Sanjian Trading Tetrahydrofuran 250ml / Solvents Yanrui Chemical

[0108] Add 250 ml of tetrahydrofuran to the reaction bottle, place it in a water bath and heat it to 55°C, then add 1.5 g of regorafenib, stir for 10 minutes until it is completely dissolved, then add 6.0 g of povidone K25, continue stirring at about 55°C for 10 minutes until it is dissolved. The solution is spray dried. The spray drying conditions are as follows:

[0109] Equipment parameters Parameter information Inlet air temperature 80～90℃ Air outlet temperature 45～60℃ Pump speed 18～20％ Nitrogen pressure 45％ Fan frequency 80～95％

[0110] The spray-dried product was placed in a vacuum drying oven, evacuated to -0.095Mpa, and vacuum dried at about 50°C, and samples were taken for testing at about 24h and 48h. Since the 48h was still far beyond the ICH standard, the product was dried for 72h and then sampled again for testing. The results are shown in Table 1.

[0111] Table 1. Residual solvent test results

[0112]

[0113] Tetrahydrofuran was used as the solvent. The water addition scheme (see Examples 1 and 2 for details) showed that after about 24 hours of secondary drying, the residual amount was 1500-1600 ppm, and reached the ICH requirement of 720 ppm or less after 48 hours. By increasing the water content in the solution, it could reach undetectable levels within 48 hours, which can maximize the safety of drug use for patients. However, in the scheme without water addition (see Comparative Example 1 for details), the residual amount was still exceeded after 48 hours of secondary vacuum drying after spray drying, and 418 ppm remained after 72 hours.

[0114] Figure 6 is the XRPD pattern of regorafenib in solid dispersion prepared by the method of this comparative example. Figure 2 Compared with the XRPD pattern of the raw material regorafenib before spray drying, the regorafenib in the solid dispersion prepared by the method of this comparative example is amorphous, which can effectively improve the dissolution properties of the drug regorafenib compared with the raw material regorafenib with high crystallinity. However, as compared above, the residual solvent level of Comparative Example 1 (without water addition) is much higher than that of Examples 1 and 2.

[0115] In order to demonstrate the effect of the present invention, the anti-tumor drug Sorafenib was used as a research model compound to compare the spray drying schemes with and without adding water, and the effect of removing the residual solvent after secondary drying.

[0116] Example 3

[0117] The prescription is as follows:

[0118] Name of raw materials prescription percentage Function factory Sorafenib 1.5g 20％ Active ingredients ANEJI CHEMICALS Copolyvinylpyrrolidone VA64 6.0g 80％ Solid matrix Shanghai Yuanhong Chemical Tetrahydrofuran 145ml / Solvents Yanrui Chemical water 5ml / Solvents Tap water

[0119] Add 145 ml of tetrahydrofuran and 5 ml of water to the reaction bottle, place it in a water bath and heat it to 55°C, then add 1.5 g of sorafenib, stir for 10 minutes until it is completely dissolved, then add 6.0 g of copovidone VA64, continue stirring at about 55°C for about 5 minutes until it is completely dissolved. The solution is spray dried. The spray drying conditions are as follows:

[0120]

[0121]

[0122] The spray-dried product was placed in a vacuum drying oven, evacuated to -0.095 MPa, and vacuum dried at 50°C. Samples were taken after about 24 hours to detect the residual tetrahydrofuran solvent. The results are shown in Table 2.

[0123] Figure 5 is the XRPD pattern of sorafenib in solid dispersion prepared by the method of this embodiment. Figure 1 Compared with the XRPD pattern of raw sorafenib before spray drying, the sorafenib in the solid dispersion prepared by the method of this embodiment is amorphous, which can effectively improve the dissolution properties of the drug sorafenib compared with the raw sorafenib with high crystallinity.

[0124] Comparative Example 2

[0125] The prescription is as follows:

[0126] Name of raw materials prescription percentage Function factory Sorafenib 1.5g 20％ Active ingredients ANEJI CHEMICALS Copolyvinylpyrrolidone VA64 6.0g 80％ Solid matrix Shanghai Yuanhong Chemical Tetrahydrofuran 50ml / Solvents Yanrui Chemical

[0127] Process: Add 50 ml of tetrahydrofuran to the reaction bottle, place it in a water bath and heat it to 55°C, then add 1.5 g of sorafenib, stir for 10 minutes until it is completely dissolved, then add 6.0 g of copolyvidone VA64, continue stirring at about 55°C for 10 minutes until it is completely dissolved. The solution is spray dried. The spray drying conditions are as follows:

[0128] Equipment parameters Parameter information Inlet air temperature 80～90℃ Air outlet temperature 45～60℃ Pump speed 18～20％ Nitrogen pressure 45％ Fan frequency 80～95％

[0129] The spray-dried product was placed in a vacuum drying oven, evacuated to -0.095 MPa, and vacuum dried at about 50°C. Samples were taken after about 24 hours to detect residual solvents. The results are shown in Table 2.

[0130] Table 2: Residual solvent test results

[0131]

[0132]

[0133] By using the anti-tumor drug sorafenib as a research model compound, tetrahydrofuran as a solvent, and adding water to the spray drying scheme (see Example 3 for details), the residual amount was 58ppm after secondary drying for about 24 hours. In the scheme without adding water (see Comparative Example 2 for details), the residual tetrahydrofuran after secondary vacuum drying for about 24 hours was 191ppm, which was higher than that without adding water. Therefore, adding water is also beneficial to reduce the residual tetrahydrofuran to a lower level.

[0134] Figure 7 is the XRPD pattern of sorafenib in solid dispersion prepared by the method of this comparative example. Figure 1 Compared with the XRPD pattern of raw sorafenib before spray drying, the sorafenib in the solid dispersion prepared by the method of this embodiment is amorphous, and compared with the raw sorafenib with high crystallinity, the dissolution properties of the drug sorafenib can be effectively improved. However, as compared above, the residual solvent level of comparative example 2 (without water addition scheme) is much higher than that of example 3.

[0135] The above is only a specific embodiment of the present invention, but the protection scope of the present invention is not limited thereto. Any person skilled in the art who is familiar with the technical field can easily think of changes or substitutions within the technical scope disclosed in the present invention, which should be included in the protection scope of the present invention. Therefore, the protection scope of the present invention should be based on the protection scope of the claims.

Claims

1. A method for removing residual solvent from a solid dispersion containing a heat-sensitive and poorly soluble drug, the removal method being carried out as follows: 1) dissolving the drug and carrier in a mixed solvent of an organic solvent and water, heating to 50-65° C., stirring until dissolved within no more than 1 hour, wherein the weight percentage of water in the total solvent is 3-64%, to obtain a clear solution; 2) The solution obtained in step 1) is spray-dried to prepare a solid dispersion, wherein the spray-drying parameters are as follows: 3) The solid dispersion product obtained in step 2) is vacuum dried at 40-60° C. and under a vacuum degree of >-0.09 MPa for no more than 72 hours to obtain a solid dispersion with qualified solvent residue.

2. The removal method according to claim 1, It is characterized in that The carrier is selected from copovidone VA64, povidone K25, hydroxypropyl methylcellulose acetate succinate (HPMCAS), and polyvinyl pyrrolidone.

3. The removal method according to claim 1, It is characterized in that The drugs are heat-sensitive and poorly soluble in water, including but not limited to sorafenib, regorafenib, enzalutamide, ritonavir, everolimus, troglitazone, nimodipine, and rosuvastatin calcium.

4. The removal method according to claim 1, It is characterized in that The mass ratio of the drug to the carrier is 1:2 to 1:

8.

5. The removal method according to claim 4, It is characterized in that The mass ratio of the drug to the carrier is 1:3 or 1:

4.

6. The removal method according to claim 1, It is characterized in that The organic solvent in step 1) is tetrahydrofuran, dichloromethane or acetonitrile, preferably tetrahydrofuran.

7. The removal method according to claim 1, It is characterized in that In step 3), the mixture is dried under vacuum at 45-50°C.

8. The removal method according to claim 1, It is characterized in that The vacuum degree in step 3) is >-0.1Mpa.

9. The removal method according to claim 1, It is characterized in that The vacuum drying in step 3) is not more than 48 hours.

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